Dr. Akhila Rajan receives McKnight Award

Linking fat health with brain health

The new project grew out of intriguing, but difficult-to-connect findings, Rajan said.

Large epidemiological studies in men and women have already linked mid-life obesity to increased risk for dementia. Scientists studying neurodegenerative diseases have found high rates of mutations in genes used by the mitochondria, which produce the energy that cells use to run biological processes.

“It wasn’t clear how these findings could be linked,” Rajan said. “It was like a child’s diagram of a flower: just dots, hard to make connections.”

But another potential connection emerged when Rajan surveyed molecules that arise in fat tissue but end up in the brain. When Rajan looked at these proteins between humans and fruit flies, which she uses to study how animals sense and respond to energy stores, she saw that mitochondrial proteins were among the most enriched.

Then a few years later, other researchers showed that components of fat mitochondria travel from adipose tissue to other tissues, such as the heart.

The dots were getting connected.

These findings opened intriguing new avenues of investigation. A theory emerged that perhaps mitochondrial components from fat influenced the function and health of brain cells.

Mroj Alassaf, PhD, a postdoctoral fellow in Rajan’s lab, suggested that the pieces of mitochondria that travel from fat to the brain be the mechanism that fat tissue uses to influence brain health.

“It was a provocative idea about how one organ could influence the bioenergetics of other organs,” Rajan said. “The beauty of my fly system is that you can take a provocative idea and actually test it.”

Using their fruit flies, Rajan and Alassaf found that fat mitochondrial components don’t just travel to the brain — they also integrate themselves into brain mitochondria. This was another finding that, on its face, made little sense.

“Neurons need a lot of energy, so they rely heavily on mitochondria,” Rajan said. “The brain is already enriched in mitochondria. Why would you want to send these components to the brain?”

But fat isn’t sending a mix of mitochondrial proteins; instead, it sends one protein that performs a critical function in the last step of energy production. Like any manufacturing plant, mitochondria need high-quality machinery to run smoothly. So fat cells may help brain mitochondria churn out energy more quickly and smoothly when they send pristine proteins. But when they send slightly damaged proteins, fat cells could instead be gumming up the works and slowing the energy output of brain mitochondria.

External factors appear to influence the rate at which mitochondrial proteins travel to the brain. Rajan has found that more fat mitochondrial components end up in the brain when flies eat a high-sugar diet. Rajan and others have demonstrated that long-term, high-sugar diets cause build-up of fat and behavioral changes in flies. More sugar inspires more sugar cravings in these flies.

This suggests to Rajan and Alassaf that the metabolic health of fat may change the quality of mitochondrial components it sends to the brain, and these have different effects on brain health.

“It may be that at baseline, these components have no effect, but when they are going from obese tissue to the brain, they start passing on the dysfunctions in mitochondrial biology,” Rajan said.

Why fat mitochondrial components enter the brain and how they get transported from fat cells are still questions to be explored.

“Our plan is to combine genetics in conjunction with behavioral analysis to study this phenomenon,” Rajan said. “We can get to the basic foundational biology, and if it works out as planned, we can at least identify one of the thousand mechanisms by which excess fat degrades brain function.”

Her McKnight Award will allow Rajan to learn more about how fat cells package mitochondrial components, and how those packages make their way into the brain.

To protect brain cells, our bodies tightly control what can make its way out of the blood and into the brain. It’s a major barrier for drug developers who want to design therapies to target, for example, brain tumors. Rajan’s studies will provide insights into natural strategies to accomplish this task, which could help drug developers improve their own approaches.

Her work will likely also reveal more on the far-reaching influence of fat cells’ metabolic health on the overall health of the brain and the body. Rajan’s early findings suggest that fat mitochondrial proteins may even influence sleep quality.

“We’re driven by curiosity here, and I’m not punting for a certain outcome,” Rajan said. “I’m asking the system to reveal the mechanism to me. It will be very informative either way.”

Science for the underserved

Rajan is also excited by another opportunity her McKnight funding affords: the chance to help make science — and the questions that scientists study — more inclusive.

To start with, Rajan is keenly aware that obesity and the health burdens that often accompany it impact minority populations more, and that her findings may have increased importance for people in underserved populations.

She also wants to help encourage budding scientists. Rajan plans to design science camps that will introduce hands-on neuroscience research to middle schoolers from disadvantaged backgrounds. Using flies in the research will make asking complex neurological questions much easier and more accessible, Rajan said.

“Everybody is fascinated by the idea of how do you sense satiety or fullness? What makes you sleep well? How do you fix something that’s broken?” she said. “The funding from McKnight will help us develop the experiments and make them accessible to kids.”